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Status:

COMPLETED

Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies

Lead Sponsor:

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborating Sponsors:

National Cancer Institute (NCI)

Conditions:

Hematologic Malignancies

Eligibility:

All Genders

6-75 years

Phase:

PHASE1

PHASE2

Brief Summary

If transplantation using mismatched unrelated donors or non-first-degree relatives could be performed with an acceptable toxicity profile, an important unmet need would be served. Towards this goal, t...

Eligibility Criteria

Inclusion

  • Patient
  • Patient age 0.5-75 years
  • Absence of a suitable related or unrelated bone marrow donor who is molecularly matched at HLA-A, B, Cw, DRB1, and DQB1.
  • Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor. Donors who are homozygous for the CCR5delta32 polymorphism are given preference.
  • Eligible diagnoses:
  • Relapsed or refractory acute leukemia in second or subsequent remission, with remission defined as \<5% bone marrow blasts morphologically
  • Poor-risk acute leukemia in first remission, with remission defined as \<5% bone marrow blasts morphologically:
  • AML with at least one of the following:
  • AML arising from MDS or a myeloproliferative disorder, or secondary AML
  • Presence of Flt3 internal tandem duplications
  • Poor-risk cytogenetics: Complex karyotype \[\> 3 abnormalities\], inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7
  • Primary refractory disease
  • ALL (leukemia and/or lymphoma) with at least one of the following:
  • Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement
  • Clear evidence of hypodiploidy
  • Primary refractory disease
  • Biphenotypic leukemia
  • MDS with at least one of the following poor-risk features:
  • Poor-risk cytogenetics (7/7q minus or complex cytogenetics)
  • IPSS score of INT-2 or greater
  • Treatment-related MDS
  • MDS diagnosed before age 21 years
  • Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy
  • Life-threatening cytopenias, including those generally requiring greater than weekly transfusions
  • Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase.
  • Philadelphia chromosome negative myeloproliferative disease.
  • Chronic myelomonocytic leukemia.
  • Juvenile myelomonocytic leukemia.
  • Low-grade non-Hodgkin lymphoma (including SLL and CLL) or plasma cell neoplasm that has:
  • progressed after at least two prior therapies (excluding single agent rituximab and single agent steroids), or
  • in the case of lymphoma undergone histologic conversion;
  • patients with transformed lymphomas must have stable disease or better.
  • Poor-risk CLL or SLL as follows:
  • 11q deletion disease that has progressed after a combination chemotherapy regimen,
  • 17p deletion disease,
  • or histologic conversion;
  • patients with transformed lymphomas must have stable disease or better.
  • Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or better to last therapy:
  • NK or NK-T cell lymphoma, hepatosplenic T-cell lymphoma, or subcutaneous panniculitic T-cell lymphoma, blastic/ blastoid variant of mantle cell lymphoma
  • Hodgkin or aggressive non Hodgkin lymphoma that has failed at least one multiagent regimen, and the patient is either ineligible for autologous BMT or autologous BMT is not recommended.
  • Eligible subtypes of aggressive non-Hodgkin lymphoma include:
  • mantle cell lymphoma
  • follicular grade 3 lymphoma
  • diffuse large B-cell lymphoma or its subtypes, excluding primary CNS lymphoma
  • primary mediastinal large B-cell lymphoma
  • large B-cell lymphoma, unspecified
  • anaplastic large cell lymphoma, excluding skin-only disease
  • Burkitt's lymphoma or atypical Burkitt's lymphoma (high-grade B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt's), in complete remission
  • Patients with CLL, SLL, or prolymphocytic leukemia must have \< 20% bone marrow involvement by malignancy (to lower risk of graft rejection).
  • One of the following, in order to lower risk of graft rejection:
  • Cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or alemtuzumab within 3 months prior to start of conditioning; or
  • Previous BMT within 6 months prior to start of conditioning.
  • NOTE: Patients who have received treatment outside of these windows may be eligible if it is deemed sufficient to reduce graft rejection risk; this will be decided on a case-by-case basis by the PI or co-PI.
  • Any previous BMT must have occurred at least 3 months prior to start of conditioning.
  • Adequate end-organ function as measured by:
  • Left ventricular ejection fraction greater than or equal to 35%, or shortening fraction \> 25%, unless cleared by a cardiologist
  • Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \< 5 x ULN
  • FEV1 and FVC \> 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation \>92% on room air
  • ECOG performance status \< 2 or Karnofsky or Lansky score \> 60
  • Patient

Exclusion

  • Not pregnant or breast-feeding.
  • No uncontrolled bacterial, viral, or fungal infection.
  • Note: HIV-infected patients are potentially eligible. Eligibility of HIV-infected patients will be determined on a case-by-case basis.
  • No previous allogeneic BMT (syngeneic BMT permissible).
  • Active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted.
  • Donor Inclusion Criteria:
  • Potential donors consist of:
  • Unrelated donors
  • Second-degree relatives
  • First cousins
  • The donor and recipient must be identical at at least 5 HLA alleles based on high resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched for a class II gene (HLA-DRB1 or -DQB1).
  • Meets institutional selection criteria and medically fit to donate. 4 . Lack of recipient anti-donor HLA antibody. Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors. Pheresis to reduce anti-HLA antibodies is permissible; however eligibility to proceed with the transplant regimen would be contingent upon the result.
  • Donor

Key Trial Info

Start Date :

September 1 2010

Trial Type :

INTERVENTIONAL

Allocation :

ACTUAL

End Date :

May 28 2024

Estimated Enrollment :

89 Patients enrolled

Trial Details

Trial ID

NCT01203722

Start Date

September 1 2010

End Date

May 28 2024

Last Update

April 30 2025

Active Locations (1)

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1

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States, 21231-2410